tbuckley/cabot-search huggingface dataset:
Seeing Gender Bias Through a Corrected Lens
Authors: Keith D. Lillemoe
Journal: JAMA Surgery (2022)

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Association of Body Mass Index With the Safety Profile of Nivolumab With or Without Ipilimumab
Authors: Jennifer L. McQuade, Hans Hammers, Helena Furberg, Andreas Engert, Thierry André, George Blumenschein, Nizar Tannir, Ari Baron, James Larkin, Anthony El-Khoueiry, David P. Carbone, John-Michael Thomas, Delphine Hennicken, Mary Coffey, Robert J. Motzer
Journal: JAMA Oncology (2022)

Increased survival with immune checkpoint inhibitors has been reported for patients with obesity vs a normal body mass index (BMI). However, the association of obesity with the safety of immune checkpoint inhibitors warrants study.To investigate associations between BMI and immune-related adverse events (irAEs) among patients with advanced cancers treated with nivolumab monotherapy and nivolumab plus ipilimumab combination therapy.This study was a retrospective pooled analysis of 3772 patients from 14 multicenter CheckMate clinical trials across 8 tumor types. Patients with advanced cancers received nivolumab, 3 mg/kg (n = 2746); nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg (n = 713); or nivolumab, 1 mg/kg, plus ipilimumab, 3 mg/kg (n = 313). Baseline BMI was categorized as normal weight or underweight (<25), overweight (25 to <30), or obese (≥30) according to World Health Organization criteria. The studies began patient enrollment between February 9, 2012, and May 21, 2015, and patients were followed up to database lock on May 1, 2019. Data analysis was conducted from May 1 to September 1, 2019.Nivolumab, 3 mg/kg; nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg; and nivolumab, 1 mg/kg, plus ipilimumab, 3 mg/kg.Odds ratios (ORs) and 95% CIs for incidence of any-grade and grade 3 or 4 irAEs were calculated for patients with obesity vs normal weight or underweight BMI in the overall cohort and in subgroups based on patient and tumor characteristics. Analyses for nivolumab plus ipilimumab cohorts were exploratory.A total of 3772 patients were included, 2600 were male (69%), and median age was 61 years (range, 18-90 years). For patients receiving monotherapy with nivolumab, 3 mg/kg (n = 2746), the incidence of any-grade irAEs was higher in patients with obesity (n = 543) vs those with normal weight or underweight BMI (n = 1266; OR, 1.71; 95% CI, 1.38-2.11). Incidence of grade 3 or 4 irAEs did not differ between patients with obesity and those with normal weight or underweight BMI (OR, 1.21; 95% CI, 0.92-1.61). Risk of any-grade and grade 3 or 4 irAEs appeared consistent with that in the overall population across all subgroups evaluated except for a higher likelihood of grade 3 or 4 irAEs among female patients with obesity vs normal weight or underweight BMI (OR, 1.73; 95% CI, 1.07-2.79). For patients receiving nivolumab plus ipilimumab, the incidence of irAEs appeared consistent across BMI categories.Obesity appeared to be associated with an increased incidence of any-grade irAEs among patients treated with nivolumab monotherapy and with grade 3 or 4 irAEs among female patients only. These findings may inform the monitoring of patients at high risk of developing irAEs.
Patient preference for second- and third-line therapies in type 2 diabetes: a prespecified secondary endpoint of the TriMaster study
Authors: Beverley M. Shields, Catherine D. Angwin, Maggie H. Shepherd, Nicky Britten, Angus G. Jones, Naveed Sattar, Rury Holman, Ewan R. Pearson, Andrew T. Hattersley
Journal: Nature Medicine (2022)
Colorectal sessile serrated lesion detection using linked-color imaging versus narrow-band imaging: a parallel randomized controlled trial
Authors: Jun Li, Kan Chen, Yunlei Wei, Di Zhang, Yuxin Wang, Xiaojia Hou, Ruijin Wu, Kangsheng Peng, Lei Li, Chao Huang, Yilong Wang, Linjuan Xun, Feng Liu
Journal: Endoscopy (2022)

Background Previous studies have reported the effectiveness of narrow-band imaging (NBI) and linked-color imaging (LCI) in improving the detection of colorectal neoplasms. There has however been no direct comparison between LCI and NBI in the detection of colorectal sessile serrated lesions (SSLs). The present study aimed to compare the effectiveness of LCI and NBI in detecting colorectal SSLs. Methods A prospective, parallel, randomized controlled trial was conducted. The participants were randomly assigned to the LCI or NBI arms. The primary end point was the SSL detection rate (SDR). Results 406 patients were involved; 204 in the LCI arm and 202 in the NBI arm. The total polyp detection rate, adenoma detection rate, and SDR were 54.2 %, 38.7 %, and 10.8%, respectively. The SDR was not significantly different between the LCI and NBI arms (12.3 % vs. 9.4 %; P = 0.36). The differences in the detection rate and the per-patient number of polyps, adenomas, diminutive lesions, and flat lesions between LCI and NBI also were not statistically significant. Multivariate analysis showed that LCI and NBI were not independent factors associated with SDR, whereas Boston Bowel Preparation Scale score (odds ratio [OR] 1.35, 95 %CI 1.03–1.76; P = 0.03), withdrawal time (OR 1.13, 95 %CI 1.00–1.26; P = 0.04), and operator experience (OR 3.73, 95 %CI 1.67–8.32; P = 0.001) were independent factors associated with SDR. Conclusions LCI and NBI are comparable for SSL detection, as well as for the detection of polyps and adenomas.
CHIP Happens: Clonal Hematopoiesis of Indeterminate Potential and Its Relationship to Solid Tumors
Authors: Sarah C. Reed, Sarah Croessmann, Ben Ho Park
Journal: Clinical Cancer Research (2022)

Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the expansion of hematopoietic cells harboring leukemia-associated somatic mutations in otherwise healthy people and occurs in at least 10% of adults over 70. It is well established that people with CHIP have increased rates of hematologic malignancy, increased risk of cardiovascular disease, and worse all-cause mortality compared with those without CHIP. Despite recent advancements in understanding CHIP as it relates to these known outcomes, much remains to be learned about the development and role of CHIP in other disease states. Emerging research has identified high rates of CHIP in patients with solid tumors, driven in part by oncologic therapy, and revealed associations between CHIP and differential outcomes in both solid tumors and other diseases. Recent studies have demonstrated that CHIP can contribute to dysregulated inflammatory signaling in multiple contexts, underscoring the importance of interrogating how CHIP might alter tumor immunology. Here, we review the role of CHIP mutations in clonal expansion of hematopoietic cells, explore the relationship between CHIP and solid tumors, and discuss the potential roles of CHIP in inflammation and solid tumor biology.
Genomic diversity of <i>Helicobacter pylori</i> populations from different regions of the human stomach
Authors: Daniel James Wilkinson, Benjamin Dickins, Karen Robinson, Jody Anne Winter
Journal: Gut Microbes (2022)

Individuals infected with Helicobacter pylori harbor unique and diverse populations of quasispecies, but diversity between and within different regions of the human stomach and the process of bacterial adaptation to each location are not yet well understood. We applied whole-genome deep sequencing to characterize the within- and between-stomach region genetic diversity of H. pylori populations from paired antrum and corpus biopsies of 15 patients, along with single biopsies from one region of an additional 3 patients, by scanning allelic diversity. We combined population deep sequencing with more conventional sequencing of multiple H. pylori single colony isolates from individual biopsies to generate a unique dataset. Single colony isolates were used to validate the scanning allelic diversity pipelines. We detected extensive population allelic diversity within the different regions of each patient's stomach. Diversity was most commonly found within non-coding, hypothetical, outer membrane, restriction modification system, virulence, lipopolysaccharide biosynthesis, efflux systems, and chemotaxis-associated genes. Antrum and corpus populations from the same patient grouped together phylogenetically, indicating that most patients were initially infected with a single strain, which then diversified. Single colonies from the antrum and corpus of the same patients grouped into distinct clades, suggesting mechanisms for within-location adaptation across multiple H. pylori isolates from different patients. The comparisons made available by combined sequencing and analysis of isolates and populations enabled comprehensive analysis of the genetic changes associated with H. pylori diversification and stomach region adaptation.
Comparison of Male and Female Surgeons’ Experiences With Gender Across 5 Qualitative/Quantitative Domains
Authors: Cheryl K. Zogg, Lyndsay A. Kandi, Hannah S. Thomas, Mary A. Siki, Ashley Y. Choi, Camila R. Guetter, Charlotte B. Smith, Erica Maduakolam, Shreya Kondle, Sharon L. Stein, Elizabeth A. Shaughnessy, Nita Ahuja
Journal: JAMA Surgery (2022)

A growing body of literature has been developed with the goal of attempting to understand the experiences of female surgeons. While it has helped to address inequities and promote important programmatic improvements, work remains to be done.To explore how practicing male and female surgeons' experiences with gender compare across 5 qualitative/quantitative domains: career aspirations, gender-based discrimination, mentor-mentee relationships, perceived barriers, and recommendations for change.This national concurrent mixed-methods survey of Fellows of the American College of Surgeons (FACS) compared differences between male and female FACS. Differences between female FACS and female members of the Association of Women Surgeons (AWS) were also explored. A randomly selected 3:1 sample of US-based male and female FACS was surveyed between January and June 2020. Female AWS members were surveyed in May 2020.Self-reported gender.Self-reported experiences with career aspirations (quantitative), gender-based discrimination (quantitative), mentor-mentee relationships (quantitative), perceived barriers (qualitative), and recommendations for change (qualitative).A total of 2860 male FACS (response rate: 38.1% [2860 of 7500]) and 1070 female FACS (response rate: 42.8% [1070 of 2500]) were included, in addition to 536 female AWS members. Demographic characteristics were similar between randomly selected male and female FACS, with the notable exception that female FACS were less likely to be married (720 [67.3%] vs 2561 [89.5%]; nonresponse-weighted P < .001) and have children (660 [61.7%] vs 2600 [90.9%]; P < .001). Compared with female FACS, female AWS members were more likely to be younger and hold additional graduate degrees (320 [59.7%] were married; 238 [44.4%] had children). FACS of both genders acknowledged positive and negative aspects of dealing with gender in a professional setting, including shared experiences of gender-based harassment, discrimination, and blame. Female FACS were less likely to have had gender-concordant mentors. They were more likely to emphasize the importance of gender when determining career aspirations and prioritizing future mentor-mentee relationships. Moving forward, female FACS emphasized the importance of avoiding competition among female surgeons. They encouraged male surgeons to acknowledge gender bias and admit their potential role. Male FACS encouraged male and female surgeons to treat everyone the same.Experiences with gender are not limited to supportive female surgeons. The results of this study emphasize the importance of recognizing the voices of all stakeholders involved when striving to promote workforce diversity and the related need to develop quality improvement/surgical education initiatives that enhance inclusion through open, honest discourse.
Clarification of Conflict of Interest Disclosures
Authors: Juliana Kim, Stephanie Savory, Shadmehr Demehri, Jennifer Gill
Journal: JAMA Dermatology (2022)

Kanthi Bommareddy, MD; Hassan Hamade, MD; Maria A. Lopez-Olivo, MD, PhD, MSc; Mackenzie Wehner, MD, MPhil; Traci Tosh, MSIS; John S. Barbieri, MD, MBA
High‐Yield Production of Extracellular Vesicle Subpopulations with Constant Quality Using Batch‐Refeed Cultures
Authors: Carolina Paganini, Hannah Boyce, Gabriela Libort, Paolo Arosio
Journal: Advanced Healthcare Materials (2022)

The conventional manufacturing of extracellular vesicles (EVs) is characterized by low yields and batch-to-batch variability, hampering fundamental research on EVs and their practical applications. Perfusion operations have huge potential to address these limitations and increase the productivity and quality of EVs. In this study, perfusion cultures are simulated with batch-refeed systems and their productivity is compared with that achieved using batch cultures. It is shown that a shift from batch to batch-refeed system can increase the space-time yields of a target EV subpopulation characterized by CD81 and CD63 biomarkers by threefold. Moreover, it is demonstrated that the method facilitates the consistent production of the target EVs from cells maintained under constant conditions for 13 days. These results indicate that the use of perfusion cultures is a promising strategy to increase the manufacturing yield of EVs and control the production of specific EV subpopulations with constant quality attributes, thereby improving reproducibility.
Protein Phosphatase 1 Subunit PPP1R14B Stabilizes STMN1 to Promote Progression and Paclitaxel Resistance in Triple-Negative Breast Cancer
Authors: Li Liao, Yin-Ling Zhang, Ling Deng, Chao Chen, Xiao-Yan Ma, Lisa Andriani, Shao-Ying Yang, Shu-Yuan Hu, Fang-Lin Zhang, Zhi-Min Shao, Da-Qiang Li
Journal: Cancer Research (2022)

Triple-negative breast cancer (TNBC) represents the most lethal subtype of breast cancer due to its aggressive clinical features and the lack of effective therapeutic targets. To identify novel approaches for targeting TNBC, we examined the role of protein phosphatases in TNBC progression and chemoresistance. Protein phosphatase 1 regulatory subunit 14B (PPP1R14B), a poorly defined member of the protein phosphatase 1 regulatory subunits, was aberrantly upregulated in TNBC tissues and predicted poor prognosis. PPP1R14B was degraded mainly through the ubiquitin-proteasome pathway. RPS27A recruited deubiquitinase USP9X to deubiquitinate and stabilize PPP1R14B, resulting in overexpression of PPP1R14B in TNBC tissues. Gain- and loss-of-function assays demonstrated that PPP1R14B promoted TNBC cell proliferation, colony formation, migration, invasion, and resistance to paclitaxel in vitro. PPP1R14B also induced xenograft tumor growth, lung metastasis, and paclitaxel resistance in vivo. Mechanistic investigations revealed that PPP1R14B maintained phosphorylation and stability of oncoprotein stathmin 1 (STMN1), a microtubule-destabilizing phosphoprotein critically involved in cancer progression and paclitaxel resistance, which was dependent on PP1 catalytic subunits α and γ. Importantly, the tumor-suppressive effects of PPP1R14B deficiency could be partially rescued by ectopic expression of wild-type but not phosphorylation-deficient STMN1. Moreover, PPP1R14B decreased STMN1-mediated α-tubulin acetylation, microtubule stability, and promoted cell-cycle progression, leading to resistance of TNBC cells to paclitaxel. Collectively, these findings uncover a functional and mechanistic role of PPP1R14B in TNBC progression and paclitaxel resistance, indicating PPP1R14B is a potential therapeutic target for TNBC.PPP1R14B upregulation induced by RPS27A/USP9X in TNBC increases STMN1 activity, leading to cancer progression and paclitaxel resistance.
Convergent Approaches to Delineate the Metabolic Regulation of Tumor Invasion by Hyaluronic Acid Biosynthesis
Authors: Adrian A. Shimpi, Matthew L. Tan, Michael Vilkhovoy, David Dai, LaDeidra Monet Roberts, Joe Chin‐Hun Kuo, Lingting Huang, Jeffrey D. Varner, Matthew Paszek, Claudia Fischbach
Journal: Advanced Healthcare Materials (2022)

Metastasis is the leading cause of breast cancer-related deaths and is often driven by invasion and cancer-stem like cells (CSCs). Both the CSC phenotype and invasion are associated with increased hyaluronic acid (HA) production. How these independent observations are connected, and which role metabolism plays in this process, remains unclear due to the lack of convergent approaches integrating engineered model systems, computational tools, and cancer biology. Using microfluidic invasion models, metabolomics, computational flux balance analysis, and bioinformatic analysis of patient data, the functional links between the stem-like, invasive, and metabolic phenotype of breast cancer cells as a function of HA biosynthesis are investigated. These results suggest that CSCs are more invasive than non-CSCs and that broad metabolic changes caused by overproduction of HA play a role in this process. Accordingly, overexpression of hyaluronic acid synthases (HAS) 2 or 3 induces a metabolic phenotype that promotes cancer cell stemness and invasion in vitro and upregulates a transcriptomic signature predictive of increased invasion and worse patient survival. This study suggests that HA overproduction leads to metabolic adaptations to satisfy the energy demands for 3D invasion of breast CSCs highlighting the importance of engineered model systems and multidisciplinary approaches in cancer research.
Fine-Mapping and Comparative Genomic Analysis Reveal the Gene Composition at the<i>S</i>and<i>Z</i>Self-incompatibility Loci in Grasses
Authors: Marius Rohner, Chloé Manzanares, Steven Yates, Daniel Thorogood, Dario Copetti, Thomas Lübberstedt, Torben Asp, Bruno Studer
Journal: Molecular Biology and Evolution (2022)

Self-incompatibility (SI) is a genetic mechanism of hermaphroditic plants to prevent inbreeding after self-pollination. Allogamous Poaceae species exhibit a unique gametophytic SI system controlled by two multi-allelic and independent loci, S and Z. Despite intense research efforts in the last decades, the genes that determine the initial recognition mechanism are yet to be identified. Here, we report the fine-mapping of the Z-locus in perennial ryegrass (Lolium perenne L.) and provide evidence that the pollen and stigma components are determined by two genes encoding DUF247 domain proteins (ZDUF247-I and ZDUF247-II) and the gene sZ, respectively. The pollen and stigma determinants are located side-by-side and were genetically linked in 10,245 individuals of two independent mapping populations segregating for Z. Moreover, they exhibited high allelic diversity as well as tissue-specific gene expression, matching the expected characteristics of SI determinants known from other systems. Revisiting the S-locus using the latest high-quality whole-genome assemblies revealed a similar gene composition and structure as found for Z, supporting the hypothesis of a duplicated origin of the two-locus SI system of grasses. Ultimately, comparative genomic analyses across a wide range of self-compatible and self-incompatible Poaceae species revealed that the absence of a functional copy of at least one of the six putative SI determinants is accompanied by a self-compatible phenotype. Our study provides new insights into the origin and evolution of the unique gametophytic SI system in one of the largest and economically most important plant families.
Deep Learning for Cross-Diagnostic Prediction of Mental Disorder Diagnosis and Prognosis Using Danish Nationwide Register and Genetic Data
Authors: Rosa Lundbye Allesøe, Wesley K. Thompson, Jonas Bybjerg-Grauholm, David M. Hougaard, Merete Nordentoft, Thomas Werge, Simon Rasmussen, Michael Eriksen Benros
Journal: JAMA Psychiatry (2022)

Diagnoses and treatment of mental disorders are hampered by the current lack of objective markers needed to provide a more precise diagnosis and treatment strategy.To develop deep learning models to predict mental disorder diagnosis and severity spanning multiple diagnoses using nationwide register data, family and patient-specific diagnostic history, birth-related measurement, and genetics.This study was conducted from May 1, 1981, to December 31, 2016. For the analysis, which used a Danish population-based case-cohort sample of individuals born between 1981 and 2005, genotype data and matched longitudinal health register data were taken from the longitudinal Danish population-based Integrative Psychiatric Research Consortium 2012 case-cohort study. Included were individuals with mental disorders (attention-deficit/hyperactivity disorder [ADHD]), autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), schizophrenia spectrum disorders (SCZ), and population controls. Data were analyzed from February 1, 2021, to January 24, 2022.At least 1 hospital contact with diagnosis of ADHD, ASD, MDD, BD, or SCZ.The predictability of (1) mental disorder diagnosis and (2) severity trajectories (measured by future outpatient hospital contacts, admissions, and suicide attempts) were investigated using both a cross-diagnostic and single-disorder setup. Predictive power was measured by AUC, accuracy, and Matthews correlation coefficient (MCC), including an estimate of feature importance.A total of 63 535 individuals (mean [SD] age, 23 [7] years; 34 944 male [55%]; 28 591 female [45%]) were included in the model. Based on data prior to diagnosis, the specific diagnosis was predicted in a multidiagnostic prediction model including the background population with an overall area under the curve (AUC) of 0.81 and MCC of 0.28, whereas the single-disorder models gave AUCs/MCCs of 0.84/0.54 for SCZ, 0.79/0.41 for BD, 0.77/0.39 for ASD, 0.74/0.38, for ADHD, and 0.74/0.38 for MDD. The most important data sets for multidiagnostic prediction were previous mental disorders and age (11%-23% reduction in prediction accuracy when removed) followed by family diagnoses, birth-related measurements, and genetic data (3%-5% reduction in prediction accuracy when removed). Furthermore, when predicting subsequent disease trajectories of the disorder, the most severe cases were the most easily predictable, with an AUC of 0.72.Results of this diagnostic study suggest the possibility of combining genetics and registry data to predict both mental disorder diagnosis and disorder progression in a clinically relevant, cross-diagnostic setting prior to clinical assessment.